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9c6x
From Proteopedia
Crystal Structure of a single chain trimer composed of HLA-B*39:01 Y84C variant, beta-2microglobulin, and NRVMLPKAA peptide from NLRP2
Structural highlights
DiseaseNALP2_HUMAN The disease is caused by variants affecting the gene represented in this entry.B2MG_HUMAN Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:241600. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation.[1] Note=Beta-2-microglobulin may adopt the fibrillar configuration of amyloid in certain pathologic states. The capacity to assemble into amyloid fibrils is concentration dependent. Persistently high beta(2)-microglobulin serum levels lead to amyloidosis in patients on long-term hemodialysis.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] FunctionR5AK10_HUMAN NALP2_HUMAN Suppresses TNF- and CD40-induced NFKB1 activity at the level of the IKK complex, by inhibiting NFKBIA degradation induced by TNF. When associated with PYCARD, activates CASP1, leading to the secretion of mature pro-inflammatory cytokine IL1B. May be a component of the inflammasome, a protein complex which also includes PYCARD, CARD8 and CASP1 and whose function would be the activation of pro-inflammatory caspases.[15] B2MG_HUMAN Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system. Publication Abstract from PubMedType 1 diabetes (T1D) is an autoimmune disease involving T cell-mediated destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans. CD8(+) T cells, responding to beta cell peptides presented by class I major histocompatibility complex (MHC) molecules, are important effectors leading to beta cell elimination. Human leukocyte antigen (HLA) B*39:06, B*39:01, and B*38:01 are closely related class I MHC allotypes that nonetheless show differential association with T1D. HLA-B*39:06 is the most predisposing of all HLA class I molecules and is associated with early age at disease onset. B*39:01 is also associated with susceptibility to T1D, but to a lesser extent, though differing from B*39:06 by only two amino acids. HLA-B*38:01, in contrast, is associated with protection from the disease. Upon identifying a peptide that binds to both HLA-B*39:06 and B*39:01, we determined the respective X-ray structures of the two allotypes presenting this peptide to 1.7 A resolution. The peptide residues available for T cell receptor contact and those serving as anchors were identified. Analysis of the F pocket of HLA-B*39:06 and B*39:01 provided an explanation for the distinct peptide C-terminus preferences of the two allotypes. Structure-based modeling of the protective HLA-B*38:01 suggested a potential reason for its peptide preferences and its reduced propensity to present 8-mer peptides compared to B*39:06. Notably, the three allotypes showed differential binding to peptides derived from beta cell autoantigens. Taken together, our findings should facilitate identification of disease-relevant candidate T cell epitopes and structure-guided therapeutics to interfere with peptide binding. Structural and biochemical analysis of highly similar HLA-B allotypes differentially associated with type 1 diabetes.,Sharma R, Amdare NP, Ghosh A, Schloss J, Sidney J, Garforth SJ, Lopez Y, Celikgil A, Sette A, Almo SC, DiLorenzo TP J Biol Chem. 2024 Aug 20:107702. doi: 10.1016/j.jbc.2024.107702. PMID:39173948[16] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Almo SC | Amdare NP | Celikgil A | DiLorenzo TP | Garforth SJ | Ghosh A | Sharma R
